Understanding changes in the expression of genes involved in regulating various components of the neural extracellular matrix (ECM) during aging can provide an insight into aging-associated decline in synaptic and cognitive functions. Hence, in this study, we compared the expression levels of ECM-related genes in the hippocampus of young, aged and very aged mice. ECM gene expression was downregulated, despite the accumulation of ECM proteoglycans during aging. The most robustly downregulated gene was carbohydrate sulfotransferase 3 (Chst3), the enzyme responsible for the chondroitin 6-sulfation (C6S) of proteoglycans. Further analysis of epigenetic mechanisms revealed a decrease in H3K4me3, three methyl groups at the lysine 4 on the histone H3 proteins, associated with the promoter region of the Chst3 gene, resulting in the downregulation of Chst3 expression in non-neuronal cells. Cluster analysis revealed that the expression of lecticans—substrates of CHST3—is tightly co-regulated with this enzyme. These changes in ECM-related genes were accompanied by an age-confounded decline in cognitive performance. Despite the co-directional impairment in cognitive function and average Chst3 expression in the studied age groups, at the individual level we found a negative correlation between mRNA levels of Chst3 and cognitive performance within the very aged group. An analysis of correlations between the expression of ECM-related genes and cognitive performance in novel object versus novel location recognition tasks revealed an apparent trade-off in the positive gene effects in one task at the expense of another. Further analysis revealed that, despite the reduction in the Chst3 mRNA, the expression of CHST3 protein is increased in glial cells but not in neurons, which, however, does not lead to changes in the absolute level of C6S and even results in the decrease in C6S in perineuronal, perisynaptic and periaxonal ECM relative to the elevated expression of its protein carrier versican.

Humans and others primates are highly attuned to temporal consistencies and regularities in their sensory environment and learn to predict such statistical structure. Moreover, in several instances, the presence of temporal structure has been found to facilitate procedural learning and to improve task performance. Here we extend these findings to visual object recognition and to presentation sequences in which mutually predictive objects form distinct clusters or “communities.” Our results show that temporal community structure accelerates recognition learning and affects the order in which objects are learned (“onset of familiarity”).

The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also around synapses and in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, perisynaptically, and at the nodes of Ranvier and the AIS, highlighting its potential role in regulating axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, Western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AISs and regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulation of aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of ankyrin-G in the AIS, particularly in excitatory neurons, and with the elevated expression of Na_v1.6 channels. Our results suggest that Ncan regulates the expression of key proteins in PNNs and AISs and provide new insights into its role in fine-tuning neuronal functions.

The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, nodes of Ranvier and the AIS, highlighting its potential role in regulation of axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AIS and in the regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulated Aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of Ankyrin-G in the AIS particularly in excitatory neurons, and with the elevated expression of Na _v 1.6 channels. Our results suggest that Ncan regulate expression of key proteins in PNNs and AISs and provide new insights into its role in the fine-tuning of neuronal functions.